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1. Coproduction of accessible digital mental health supports in partnership with young people from marginalised backgrounds: a scoping review protocol

Author

Siobhan O'Neill, Gary Donohoe, Carmen Kealy, Courtney Potts, Maurice D Mulvenna, and Margaret M Barry

Subjects
Medicine
Abstract

Introduction Despite the evidence supporting the value of digital supports for enhancing youth mental health services, there is a lack of guidance on how best to engage with young people in coproduction processes during the design and evaluation of these technologies. User input is crucial in digital mental health, especially for disadvantaged, vulnerable and marginalised young people as they are often excluded from coproduction. A scoping review of international literature written in English will explore the coproduction processes with marginalised young people in digital mental health supports, from mental health promotion to targeted interventions. The review is guided by the research question: what are the most appropriate coproduction processes for engaging young people, especially marginalised young people, in the different stages of designing and evaluating digital mental health supports? The review aims to map and summarise the evidence, inform the overall research project and address the knowledge gaps.Methods and analysis The scoping review uses Arksey and O’Malley’s framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols Extension for Scoping Reviews. From 22–24 October 2023, PubMed, Scopus, EBSCO, ASSIA, Web of Science, Ovid MEDLINE, Cochrane database, Embase, Google Scholar, ProQuest, OAIster and BASE will be systematically searched. Papers from 2021 onwards with a range of study designs and evidence that illustrate engagement with marginalised young people (aged 16–25) in the design, implementation and evaluation of digital technologies for young people’s mental health will be considered for inclusion. At least two reviewers will screen full texts and chart data. The results of this review will be summarised quantitatively through numerical counts of included literature and qualitatively through a narrative synthesis.Ethics and dissemination Ethical approval is not required. Results will be disseminated through publications in peer-reviewed journals.Trial registration number This scoping review protocol has been registered with the Open Science Framework (https://osf.io/9xhgv).

Published
2024
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2. Uncinate fasciculus microstructural organisation and emotion recognition in schizophrenia: controlling for hit rate bias

Author

Matthew Stevens, Síle Ní Mhurchú, Emma Corley, Ciara Egan, Brian Hallahan, Colm McDonald, Gary Donohoe, and Tom Burke

Subjects
cognition, uncinate fasciculus, schizophrenia, emotion recognition, unbiased hit rate, childhood trauma, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

IntroductionSchizophrenia (SCZ) is a complex neurodevelopmental disorder characterised by functional and structural brain dysconnectivity and disturbances in perception, cognition, emotion, and social functioning. In the present study, we investigated whether the microstructural organisation of the uncinate fasciculus (UF) was associated with emotion recognition (ER) performance. Additionally, we investigated the usefulness of an unbiased hit rate (UHR) score to control for response biases (i.e., participant guessing) during an emotion recognition task (ERT).MethodsFifty-eight individuals diagnosed with SCZ were included. The CANTAB ERT was used to measure social cognition. Specific ROI manual tract segmentation was completed using ExploreDTI and followed the protocol previously outlined by Coad et al. (2020).ResultsWe found that the microstructural organisation of the UF was significantly correlated with physical neglect and ER outcomes. Furthermore, we found that the UHR score was more sensitive to ERT subscale emotion items than the standard HR score. Finally, given the association between childhood trauma (in particular childhood neglect) and social cognition in SCZ, a mediation analysis found evidence that microstructural alterations of the UF mediated an association between childhood trauma and social cognitive performance.DiscussionThe mediating role of microstructural alterations in the UF on the association between childhood trauma and social cognitive performance suggests that early life adversity impacts both brain development and social cognitive outcomes for people with SCZ. Limitations of the present study include the restricted ability of the tensor model to correctly assess multi-directionality at regions where fibre populations intersect.

Published
2024
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3. Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia

Author

Sinead King, David Mothersill, Laurena Holleran, Saahithh Redddi Patlola, Tom Burke, Ross McManus, Marcus Kenyon, Colm McDonald, Brian Hallahan, Aiden Corvin, Derek W. Morris, John P. Kelly, Declan P. McKernan, and Gary Donohoe

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Published
2023
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4. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita

Subjects
Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Published
2023
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5. Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

Author

Stephen Burgess, Peter Jones, Rachel Upthegrove, Carmine Pariante, Graham K Murray, Anthony David, Martin Wilson, Nicholas Barnes, Paola Dazzan, John Suckling, Valeria Mondelli, Muzaffer Kaser, Neil Harrison, Georgios Gkoutos, Golam M Khandaker, Deepak Jadon, James MacCabe, Gary Donohoe, Alice Egerton, Bill Deakin, Jack Rogers, Éimear M Foley, Sian Lowri Griffiths, Alexander Murray, Fabiana Corsi-Zuelli, Hannah Hickinbotham, Ella Warwick, Nicholas M Barnes, Golam Khandaker, David Cotter, Ed Bullmore, Eva Meisenzahl, Joanna Neill, Nikos Koutsouleris, and Stephen Wood

Subjects
Medicine
Abstract

Introduction Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.Methods and analysis A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6

Published
2023
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6. Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia

Author

Sinead King, David Mothersill, Laurena Holleran, Saahithh Patlola, Ross McManus, Marcus Kenyon, Colm McDonald, Brian Hallahan, Aiden Corvin, Derek W. Morris, John P. Kelly, Declan McKernan, and Gary Donohoe

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown. Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN. Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (

Published
2022
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7. Microglial-expressed genetic risk variants, cognitive function and brain volume in patients with schizophrenia and healthy controls

Author

Emma Corley, Laurena Holleran, Laura Fahey, Aiden Corvin, Derek W. Morris, and Gary Donohoe

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Changes in immune function are associated with variance in cognitive functioning in schizophrenia. Given that microglia are the primary innate immune cells in the brain, we examined whether schizophrenia risk-associated microglial genes (measured via polygenic score analysis) explained variation in cognition in patients with schizophrenia and controls (n = 1,238) and tested whether grey matter mediated this association. We further sought to replicate these associations in an independent sample of UK Biobank participants (n = 134,827). We then compared the strength of these microglial associations to that of neuronal and astroglial (i.e., other brain-expressed genes) polygenic scores, and used MAGMA to test for enrichment of these gene-sets with schizophrenia risk. Increased microglial schizophrenia polygenic risk was associated with significantly lower performance across several measures of cognitive functioning in both samples; associations which were then found to be mediated via total grey matter volume in the UK Biobank. Unlike neuronal genes which did show evidence of enrichment, the microglial gene-set was not significantly enriched for schizophrenia, suggesting that the relevance of microglia may be for neurodevelopmental processes related more generally to cognition. Further, the microglial polygenic score was associated with performance on a range of cognitive measures in a manner comparable to the neuronal schizophrenia polygenic score, with fewer cognitive associations observed for the astroglial score. In conclusion, our study supports the growing evidence of the importance of immune processes to understanding cognition and brain structure in both patients and in the healthy population.

Published
2021
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8. Counting the Toll of Inflammation on Schizophrenia—A Potential Role for Toll-like Receptors

Author

Saahithh Redddi Patlola, Gary Donohoe, and Declan P. McKernan

Subjects
inflammation, Toll-like receptor, schizophrenia, cognition, Microbiology, QR1-502
Abstract

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer’s, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.

Published
2023
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9. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Ida E. Sønderby, Dennis van der Meer, Clara Moreau, Tobias Kaufmann, G. Bragi Walters, Maria Ellegaard, Abdel Abdellaoui, David Ames, Katrin Amunts, Micael Andersson, Nicola J. Armstrong, Manon Bernard, Nicholas B. Blackburn, John Blangero, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Robin Bülow, Rune Bøen, Wiepke Cahn, Vince D. Calhoun, Svenja Caspers, Christopher R. K. Ching, Sven Cichon, Simone Ciufolini, Benedicto Crespo-Facorro, Joanne E. Curran, Anders M. Dale, Shareefa Dalvie, Paola Dazzan, Eco J. C. de Geus, Greig I. de Zubicaray, Sonja M. C. de Zwarte, Sylvane Desrivieres, Joanne L. Doherty, Gary Donohoe, Bogdan Draganski, Stefan Ehrlich, Else Eising, Thomas Espeseth, Kim Fejgin, Simon E. Fisher, Tormod Fladby, Oleksandr Frei, Vincent Frouin, Masaki Fukunaga, Thomas Gareau, Tian Ge, David C. Glahn, Hans J. Grabe, Nynke A. Groenewold, Ómar Gústafsson, Jan Haavik, Asta K. Haberg, Jeremy Hall, Ryota Hashimoto, Jayne Y. Hehir-Kwa, Derrek P. Hibar, Manon H. J. Hillegers, Per Hoffmann, Laurena Holleran, Avram J. Holmes, Georg Homuth, Jouke-Jan Hottenga, Hilleke E. Hulshoff Pol, Masashi Ikeda, Neda Jahanshad, Christiane Jockwitz, Stefan Johansson, Erik G. Jönsson, Niklas R. Jørgensen, Masataka Kikuchi, Emma E. M. Knowles, Kuldeep Kumar, Stephanie Le Hellard, Costin Leu, David E. J. Linden, Jingyu Liu, Arvid Lundervold, Astri Johansen Lundervold, Anne M. Maillard, Nicholas G. Martin, Sandra Martin-Brevet, Karen A. Mather, Samuel R. Mathias, Katie L. McMahon, Allan F. McRae, Sarah E. Medland, Andreas Meyer-Lindenberg, Torgeir Moberget, Claudia Modenato, Jennifer Monereo Sánchez, Derek W. Morris, Thomas W. Mühleisen, Robin M. Murray, Jacob Nielsen, Jan E. Nordvik, Lars Nyberg, Loes M. Olde Loohuis, Roel A. Ophoff, Michael J. Owen, Tomas Paus, Zdenka Pausova, Juan M. Peralta, G. Bruce Pike, Carlos Prieto, Erin B. Quinlan, Céline S. Reinbold, Tiago Reis Marques, James J. H. Rucker, Perminder S. Sachdev, Sigrid B. Sando, Peter R. Schofield, Andrew J. Schork, Gunter Schumann, Jean Shin, Elena Shumskaya, Ana I. Silva, Sanjay M. Sisodiya, Vidar M. Steen, Dan J. Stein, Lachlan T. Strike, Ikuo K. Suzuki, Christian K. Tamnes, Alexander Teumer, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Anne Uhlmann, Magnus O. Ulfarsson, Dennis van ‘t Ent, Marianne B. M. van den Bree, Pierre Vanderhaeghen, Evangelos Vassos, Wei Wen, Katharina Wittfeld, Margaret J. Wright, Ingrid Agartz, Srdjan Djurovic, Lars T. Westlye, Hreinn Stefansson, Kari Stefansson, Sébastien Jacquemont, Paul M. Thompson, Ole A. Andreassen, and for the ENIGMA-CNV working group

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021
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10. Moral cognition, the missing link between psychotic symptoms and acts of violence: a cross-sectional national forensic cohort study

Author

Ken O’Reilly, Paul O’Connell, Danny O’Sullivan, Aiden Corvin, James Sheerin, Padraic O’Flynn, Gary Donohoe, Hazel McCarthy, Daniela Ambrosh, Muireann O’Donnell, Aisling Ryan, and Harry G. Kennedy

Subjects
Violence, Homicide, Schizophrenia, Moral cognition, Delusions, Hallucinations, Psychiatry, RC435-571
Abstract

Abstract Background People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence. Method We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence. Results Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence. Conclusions Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention.

Published
2019
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11. Corpus Callosum Microstructural Tract Integrity Relates to Longer Emotion Recognition Reaction Time in People with Schizophrenia

Author

Tom Burke, Christina Gleeson, Laurena Holleran, David Mothersill, Jessica Holland, Laura Costello, Ruán Kane, Declan P. McKernan, Derek W. Morris, John P. Kelly, Aiden P. Corvin, Brian P. Hallahan, Colm McDonald, and Gary Donohoe

Subjects
social cognition, schizophrenia, white matter tract integrity, corpus callosum, emotion recognition, reaction time, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Objective: Schizophrenia is a complex functionally debilitating neurodevelopmental disorder, with associated social cognitive impairment. Corpus Callosum (CC) white matter tracts deficits are reported for people with schizophrenia; however, few studies focus on interhemispheric processing relative to social cognition tasks. This study aimed to determine if a relationship between the CC and social cognition exists. Method: In this cross-section study, a sample of n = 178 typical controls and n = 58 people with schizophrenia completed measures of mentalising (Reading the Mind in the Eyes), emotion recognition outcome and reaction time (Emotion Recognition Test), and clinical symptoms (Positive and Negative Symptom Scale), alongside diffusion-based tract imaging. The CC and its subregions, i.e., the genu, body, and splenium were the regions of interest (ROI). Results: Reduced white matter tract integrity was observed in the CC for patients when compared to controls. Patients performed slower, and less accurately on emotion recognition tasks, which significantly and negatively correlated to the structural integrity of the CC genu. Tract integrity further significantly and negatively related to clinical symptomatology. Conclusions: People with schizophrenia have altered white matter integrity in the genu of the CC, compared to controls, which relates to cognitive deficits associated with recognising emotional stimuli accurately and quickly, and severity of clinical symptoms.

Published
2022
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12. The role of childhood trauma in cognitive performance in schizophrenia and bipolar disorder – A systematic review

Author

Maria R. Dauvermann and Gary Donohoe

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Childhood trauma (CT) has repeatedly been associated with cognitive deficits in patients with psychosis but many inconsistencies have been reported so that the nature of the relationship remains unclear. The purpose of this review was to better characterize the contribution of CT to cognitive deficits by considering the type, severity and frequency of childhood traumatic events and their relationships with psychosis at all stages.Relevant studies were identified via electronic and manual literature searches and included original studies that investigated the relationship between CT and higher cognitive performance or social cognitive performance in patients with schizophrenia, bipolar disorder and psychosis at all stages of the illness stages (i.e. ultra-high risk, first episode or chronic phase).Overall, a majority of studies reported that patients who experienced CT displayed deficits in general cognitive ability compared to patients with psychosis without such a history. Associations between CT and other cognitive function were more mixed. When comparing patient groups, the association between CT and cognitive function was more inconsistent in patients with chronic schizophrenia than in healthy participants, ultra-high risk individuals, first-episode patients and patients with chronic bipolar disorder.In understanding the variability in the reported relationships between CT and cognition across study populations, we highlight the variety of questionnaires used and discuss the likelihood of there being differences in cognitive function based on specific stressors, severity and frequency. Finally, we consider future research steps that may shed light on psychobiological mechanisms underlying CT and cognitive performance in patients with psychosis. Keywords: Childhood trauma, Schizophrenia, Psychosis, Cognitive function, Social cognitive function

Published
2019
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13. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

Subjects
Science
Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019
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14. A randomized controlled trial of cognitive remediation for a national cohort of forensic patients with schizophrenia or schizoaffective disorder

Author

Ken O’Reilly, Gary Donohoe, Danny O’Sullivan, Ciaran Coyle, Aiden Corvin, Padraic O’Flynn, Muireann O’Donnell, Toni Galligan, Paul O’Connell, and Harry G. Kennedy

Subjects
Schizophrenia, Forensic mental health, Cognitive remediation training, CRT, Neurocognition, Effectiveness, Psychiatry, RC435-571
Abstract

Abstract Background Evidence is accumulating that Cognitive Remediation Training (CRT) is effective for ameliorating cognitive deficits experienced by patients with schizophrenia and accompanying functional impairment. There has been no randomized controlled trial of CRT using a nationally representative population of forensic patients, despite the significant cognitive deficits frequently present within this group. Methods Sixty-five patients with schizophrenia or schizoaffective disorder were enrolled in a single blind randomized controlled trial of CRT versus treatment as usual (TAU); representing 94% of those eligible within a national forensic cohort. The primary outcome measure was the composite score of the MATRICS Consensus Cognitive Battery (MCCB). Secondary outcome measures included neurocognitive and social cognitive domains, symptoms, and ‘real world’ functioning. Patient satisfaction was examined using an exit interview. Participants were reassessed at 8 months follow up. All data were analyzed using an intention to treat design (ITT). Results For the primary outcome measure, the MCCB composite score, there were significant differences between those who participated in CRT and those receiving TAU at both end of treatment and 8 months follow up (Cohen’s d = 0.34. Significant improvements were observed in visual and working memory. Mediation analysis found that those who cognitively benefited from CRT had corresponding improved functioning, and more net positive therapeutic moves i.e. moves to units with lower security within the hospital. Ninety-six percent believed their cognitive gains positively affected their daily lives. Conclusions CRT may be an acceptable and efficacious intervention for forensic patients with schizophrenia or schizoaffective disorder. Trial registration ClinicalTrials.gov Identifier: NCT02360813. Trial registered Feb 4th 2015, last updated May 1st 2015.

Published
2019
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15. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author

Eilis Hannon, Emma L Dempster, Georgina Mansell, Joe Burrage, Nick Bass, Marc M Bohlken, Aiden Corvin, Charles J Curtis, David Dempster, Marta Di Forti, Timothy G Dinan, Gary Donohoe, Fiona Gaughran, Michael Gill, Amy Gillespie, Cerisse Gunasinghe, Hilleke E Hulshoff, Christina M Hultman, Viktoria Johansson, René S Kahn, Jaakko Kaprio, Gunter Kenis, Kaarina Kowalec, James MacCabe, Colm McDonald, Andrew McQuillin, Derek W Morris, Kieran C Murphy, Colette J Mustard, Igor Nenadic, Michael C O'Donovan, Diego Quattrone, Alexander L Richards, Bart PF Rutten, David St Clair, Sebastian Therman, Timothea Toulopoulou, Jim Van Os, John L Waddington, Wellcome Trust Case Control Consortium (WTCCC), CRESTAR consortium, Patrick Sullivan, Evangelos Vassos, Gerome Breen, David Andrew Collier, Robin M Murray, Leonard S Schalkwyk, and Jonathan Mill

Subjects
epigenetics, DNA methylation, psychosis, schizophrenia, clozapine, Medicine, Science, Biology (General), QH301-705.5
Abstract

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Published
2021
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16. Interleukin 6 predicts increased neural response during face processing in a sample of individuals with schizophrenia and healthy participants: A functional magnetic resonance imaging study

Author

David Mothersill, Sinead King, Laurena Holleran, Maria Dauvermann, Saahithh Patlola, Karolina Rokita, Ross McManus, Marcus Keynon, Colm McDonald, Brian Hallahan, Aiden Corvin, Derek Morris, John Kelly, Declan McKernan, and Gary Donohoe

Subjects
IL-6, Facial emotion recognition, fMRI, Schizophrenia, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. Methods: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. Results: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p

Published
2021
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17. Neuroharmony: A new tool for harmonizing volumetric MRI data from unseen scanners

Author

Rafael Garcia-Dias, Cristina Scarpazza, Lea Baecker, Sandra Vieira, Walter H.L. Pinaya, Aiden Corvin, Alberto Redolfi, Barnaby Nelson, Benedicto Crespo-Facorro, Colm McDonald, Diana Tordesillas-Gutiérrez, Dara Cannon, David Mothersill, Dennis Hernaus, Derek Morris, Esther Setien-Suero, Gary Donohoe, Giovanni Frisoni, Giulia Tronchin, João Sato, Machteld Marcelis, Matthew Kempton, Neeltje E.M. van Haren, Oliver Gruber, Patrick McGorry, Paul Amminger, Philip McGuire, Qiyong Gong, René S. Kahn, Rosa Ayesa-Arriola, Therese van Amelsvoort, Victor Ortiz-García de la Foz, Vince Calhoun, Wiepke Cahn, and Andrea Mechelli

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2020
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18. Prospective observational cohort study of ‘treatment as usual’ over four years for patients with schizophrenia in a national forensic hospital

Author

Melanie S. Richter, Ken O’Reilly, Danny O’Sullivan, Padraic O’Flynn, Aiden Corvin, Gary Donohoe, Ciaran Coyle, Mary Davoren, Caroline Higgins, Orla Byrne, Tina Nutley, Andrea Nulty, Kapil Sharma, Paul O’Connell, and Harry G. Kennedy

Subjects
Forensic psychiatry, Treatment, Cognition, Violence risk, DUNDRUM toolkit, Psychiatry, RC435-571
Abstract

Abstract Background We evaluated change in response to multi-modal psychosocial ‘treatment as usual’ programs offered within a forensic hospital. Methods Sixty nine patients with a diagnosis of schizophrenia or schizoaffective disorder were followed for up to four years. Patient progress was evaluated using the DUNDRUM-3, a measure of patient ability to participate and benefit from multi-modal psychosocial programs and the HCR-20 dynamic items, a measure of violence proneness. We report reliable change index (RCI) and reliable and clinically meaningful change (RMC). We assessed patients’ cognition using the MCCB, psychopathology using the PANSS. The effect of cognition and psychopathology on change in DUNDRUM-3 was examined using hierarchical multiple regression with age, gender, and baseline DUNDRUM-3 scores. Results The DUNDRUM-3 changed significantly (p

Published
2018
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19. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary

Subjects
Science
Abstract

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Published
2018
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20. Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Author

Max Lam, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, David C. Liewald, John M. Starr, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G. Eriksson, Ina Giegling, Bettina Konte, Panos Roussos, Stella Giakoumaki, Katherine E. Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K. Attix, Anna C. Need, Elizabeth T. Cirulli, Aristotle N. Voineskos, Nikos C. Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Dan E. Arking, Nikolaos Smyrnis, Robert M. Bilder, Nelson A. Freimer, Tyrone D. Cannon, Edythe London, Russell A. Poldrack, Fred W. Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A. Scult, Dwight Dickinson, Richard E. Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R. Hariri, Daniel R. Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C. Keller, Ole A. Andreassen, Ian J. Deary, David C. Glahn, Anil K. Malhotra, and Todd Lencz

Subjects
GWAS, general cognitive ability, nootropics, gene expression, neurodevelopment, synapse, calcium channel, potassium channel, cerebellum, Biology (General), QH301-705.5
Abstract

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

Published
2017
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21. Novel genetic loci associated with hippocampal volume

Author

Derrek P. Hibar, Hieab H. H. Adams, Neda Jahanshad, Ganesh Chauhan, Jason L. Stein, Edith Hofer, Miguel E. Renteria, Joshua C. Bis, Alejandro Arias-Vasquez, M. Kamran Ikram, Sylvane Desrivières, Meike W. Vernooij, Lucija Abramovic, Saud Alhusaini, Najaf Amin, Micael Andersson, Konstantinos Arfanakis, Benjamin S. Aribisala, Nicola J. Armstrong, Lavinia Athanasiu, Tomas Axelsson, Ashley H. Beecham, Alexa Beiser, Manon Bernard, Susan H. Blanton, Marc M. Bohlken, Marco P. Boks, Janita Bralten, Adam M. Brickman, Owen Carmichael, M. Mallar Chakravarty, Qiang Chen, Christopher R. K. Ching, Vincent Chouraki, Gabriel Cuellar-Partida, Fabrice Crivello, Anouk Den Braber, Nhat Trung Doan, Stefan Ehrlich, Sudheer Giddaluru, Aaron L. Goldman, Rebecca F. Gottesman, Oliver Grimm, Michael E. Griswold, Tulio Guadalupe, Boris A. Gutman, Johanna Hass, Unn K. Haukvik, David Hoehn, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Kjetil N. Jørgensen, Nazanin Karbalai, Dalia Kasperaviciute, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, David C. M. Liewald, Lorna M. Lopez, Michelle Luciano, Christine Macare, Andre F. Marquand, Mar Matarin, Karen A. Mather, Manuel Mattheisen, David R. McKay, Yuri Milaneschi, Susana Muñoz Maniega, Kwangsik Nho, Allison C. Nugent, Paul Nyquist, Loes M. Olde Loohuis, Jaap Oosterlaan, Martina Papmeyer, Lukas Pirpamer, Benno Pütz, Adaikalavan Ramasamy, Jennifer S. Richards, Shannon L. Risacher, Roberto Roiz-Santiañez, Nanda Rommelse, Stefan Ropele, Emma J. Rose, Natalie A. Royle, Tatjana Rundek, Philipp G. Sämann, Arvin Saremi, Claudia L. Satizabal, Lianne Schmaal, Andrew J. Schork, Li Shen, Jean Shin, Elena Shumskaya, Albert V. Smith, Emma Sprooten, Lachlan T. Strike, Alexander Teumer, Diana Tordesillas-Gutierrez, Roberto Toro, Daniah Trabzuni, Stella Trompet, Dhananjay Vaidya, Jeroen Van der Grond, Sven J. Van der Lee, Dennis Van der Meer, Marjolein M. J. Van Donkelaar, Kristel R. Van Eijk, Theo G. M. Van Erp, Daan Van Rooij, Esther Walton, Lars T. Westlye, Christopher D. Whelan, Beverly G. Windham, Anderson M. Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, Thomas Wolfers, Lisa R. Yanek, Jingyun Yang, Alex Zijdenbos, Marcel P. Zwiers, Ingrid Agartz, Laura Almasy, David Ames, Philippe Amouyel, Ole A. Andreassen, Sampath Arepalli, Amelia A. Assareh, Sandra Barral, Mark E. Bastin, Diane M. Becker, James T. Becker, David A. Bennett, John Blangero, Hans van Bokhoven, Dorret I. Boomsma, Henry Brodaty, Rachel M. Brouwer, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Kazima B. Bulayeva, Wiepke Cahn, Vince D. Calhoun, Dara M. Cannon, Gianpiero L. Cavalleri, Ching-Yu Cheng, Sven Cichon, Mark R. Cookson, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Michael Czisch, Anders M. Dale, Gareth E. Davies, Anton J. M. De Craen, Eco J. C. De Geus, Philip L. De Jager, Greig I. De Zubicaray, Ian J. Deary, Stéphanie Debette, Charles DeCarli, Norman Delanty, Chantal Depondt, Anita DeStefano, Allissa Dillman, Srdjan Djurovic, Gary Donohoe, Wayne C. Drevets, Ravi Duggirala, Thomas D. Dyer, Christian Enzinger, Susanne Erk, Thomas Espeseth, Iryna O. Fedko, Guillén Fernández, Luigi Ferrucci, Simon E. Fisher, Debra A. Fleischman, Ian Ford, Myriam Fornage, Tatiana M. Foroud, Peter T. Fox, Clyde Francks, Masaki Fukunaga, J. Raphael Gibbs, David C. Glahn, Randy L. Gollub, Harald H. H. Göring, Robert C. Green, Oliver Gruber, Vilmundur Gudnason, Sebastian Guelfi, Asta K. Håberg, Narelle K. Hansell, John Hardy, Catharina A. Hartman, Ryota Hashimoto, Katrin Hegenscheid, Andreas Heinz, Stephanie Le Hellard, Dena G. Hernandez, Dirk J. Heslenfeld, Beng-Choon Ho, Pieter J. Hoekstra, Wolfgang Hoffmann, Albert Hofman, Florian Holsboer, Georg Homuth, Norbert Hosten, Jouke-Jan Hottenga, Matthew Huentelman, Hilleke E. Hulshoff Pol, Masashi Ikeda, Clifford R. Jack Jr, Mark Jenkinson, Robert Johnson, Erik G. Jönsson, J. Wouter Jukema, René S. Kahn, Ryota Kanai, Iwona Kloszewska, David S. Knopman, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Hervé Lemaître, Xinmin Liu, Dan L. Longo, Oscar L. Lopez, Simon Lovestone, Oliver Martinez, Jean-Luc Martinot, Venkata S. Mattay, Colm McDonald, Andrew M. McIntosh, Francis J. McMahon, Katie L. McMahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Sebastian Mohnke, Grant W. Montgomery, Derek W. Morris, Thomas H. Mosley, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael A. Nalls, Matthias Nauck, Thomas E. Nichols, Wiro J. Niessen, Markus M. Nöthen, Lars Nyberg, Kazutaka Ohi, Rene L. Olvera, Roel A. Ophoff, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W. J. H. Penninx, G. Bruce Pike, Steven G. Potkin, Bruce M. Psaty, Simone Reppermund, Marcella Rietschel, Joshua L. Roffman, Nina Romanczuk-Seiferth, Jerome I. Rotter, Mina Ryten, Ralph L. Sacco, Perminder S. Sachdev, Andrew J. Saykin, Reinhold Schmidt, Helena Schmidt, Peter R. Schofield, Sigurdur Sigursson, Andrew Simmons, Andrew Singleton, Sanjay M. Sisodiya, Colin Smith, Jordan W. Smoller, Hilkka Soininen, Vidar M. Steen, David J. Stott, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Magda Tsolaki, Christophe Tzourio, Andre G. Uitterlinden, Maria C. Valdés Hernández, Marcel Van der Brug, Aad van der Lugt, Nic J. A. van der Wee, Neeltje E. M. Van Haren, Dennis van ’t Ent, Marie-Jose Van Tol, Badri N. Vardarajan, Bruno Vellas, Dick J. Veltman, Henry Völzke, Henrik Walter, Joanna M. Wardlaw, Thomas H. Wassink, Michael E. Weale, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Eric Westman, Tonya White, Tien Y. Wong, Clinton B. Wright, Ronald H. Zielke, Alan B. Zonderman, Nicholas G. Martin, Cornelia M. Van Duijn, Margaret J. Wright, W. T. Longstreth, Gunter Schumann, Hans J. Grabe, Barbara Franke, Lenore J. Launer, Sarah E. Medland, Sudha Seshadri, Paul M. Thompson, and M. Arfan Ikram

Subjects
Science
Abstract

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Published
2017
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22. 10Kin1day: A Bottom-Up Neuroimaging Initiative

Author

Martijn P. van den Heuvel, Lianne H. Scholtens, Hannelore K. van der Burgh, Federica Agosta, Clara Alloza, Celso Arango, Bonnie Auyeung, Simon Baron-Cohen, Silvia Basaia, Manon J. N. L. Benders, Frauke Beyer, Linda Booij, Kees P. J. Braun, Geraldo Busatto Filho, Wiepke Cahn, Dara M. Cannon, Tiffany M. Chaim-Avancini, Sandra S. M. Chan, Eric Y. H. Chen, Benedicto Crespo-Facorro, Eveline A. Crone, Udo Dannlowski, Sonja M. C. de Zwarte, Bruno Dietsche, Gary Donohoe, Stefan Du Plessis, Sarah Durston, Covadonga M. Díaz-Caneja, Ana M. Díaz-Zuluaga, Robin Emsley, Massimo Filippi, Thomas Frodl, Martin Gorges, Beata Graff, Dominik Grotegerd, Dariusz Gąsecki, Julie M. Hall, Laurena Holleran, Rosemary Holt, Helene J. Hopman, Andreas Jansen, Joost Janssen, Krzysztof Jodzio, Lutz Jäncke, Vasiliy G. Kaleda, Jan Kassubek, Shahrzad Kharabian Masouleh, Tilo Kircher, Martijn G. J. C. Koevoets, Vladimir S. Kostic, Axel Krug, Stephen M. Lawrie, Irina S. Lebedeva, Edwin H. M. Lee, Tristram A. Lett, Simon J. G. Lewis, Franziskus Liem, Michael V. Lombardo, Carlos Lopez-Jaramillo, Daniel S. Margulies, Sebastian Markett, Paulo Marques, Ignacio Martínez-Zalacaín, Colm McDonald, Andrew M. McIntosh, Genevieve McPhilemy, Susanne L. Meinert, José M. Menchón, Christian Montag, Pedro S. Moreira, Pedro Morgado, David O. Mothersill, Susan Mérillat, Hans-Peter Müller, Leila Nabulsi, Pablo Najt, Krzysztof Narkiewicz, Patrycja Naumczyk, Bob Oranje, Victor Ortiz-Garcia de la Foz, Jiska S. Peper, Julian A. Pineda, Paul E. Rasser, Ronny Redlich, Jonathan Repple, Martin Reuter, Pedro G. P. Rosa, Amber N. V. Ruigrok, Agnieszka Sabisz, Ulrich Schall, Soraya Seedat, Mauricio H. Serpa, Stavros Skouras, Carles Soriano-Mas, Nuno Sousa, Edyta Szurowska, Alexander S. Tomyshev, Diana Tordesillas-Gutierrez, Sofie L. Valk, Leonard H. van den Berg, Theo G. M. van Erp, Neeltje E. M. van Haren, Judith M. C. van Leeuwen, Arno Villringer, Christiaan H. Vinkers, Christian Vollmar, Lea Waller, Henrik Walter, Heather C. Whalley, Marta Witkowska, A. Veronica Witte, Marcus V. Zanetti, Rui Zhang, and Siemon C. de Lange

Subjects
MRI, connectome analysis, diffusion weighted MRI, brain, network, Neurology. Diseases of the nervous system, RC346-429
Abstract

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Published
2019
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23. Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability.

Author

Isabella Cera, Laura Whitton, Gary Donohoe, Derek W Morris, Georg Dechant, and Galina Apostolova

Subjects
Genetics, QH426-470
Abstract

During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population.

Published
2019
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24. Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

Author

Laura Whitton, Galina Apostolova, Dietmar Rieder, Georg Dechant, Stephen Rea, Gary Donohoe, and Derek W Morris

Subjects
Genetics, QH426-470
Abstract

SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used data from Satb2 mouse models to generate three gene-sets that contain genes either functionally related to SATB2 or targeted by SATB2 at different stages of development. Each was tested for enrichment using the largest available genome-wide association studies (GWAS) datasets for schizophrenia and educational attainment (EA) and enrichment analysis was also performed for schizophrenia and other neurodevelopmental disorders using data from rare variant sequencing studies. These SATB2 gene-sets were enriched for genes containing common variants associated with schizophrenia and EA, and were enriched for genes containing rare variants reported in studies of schizophrenia, autism and intellectual disability. In the developing cortex, genes targeted by SATB2 based on ChIP-seq data, and functionally affected when SATB2 is not expressed based on differential expression analysis using RNA-seq data, show strong enrichment for genes associated with EA. For genes expressed in the hippocampus or at the synapse, those targeted by SATB2 are more strongly enriched for genes associated EA than gene-sets not targeted by SATB2. This study demonstrates that single gene findings from GWAS can provide important insights to pathobiological processes. In this case we find evidence that genes influenced by SATB2 and involved in synaptic transmission, axon guidance and formation of the corpus callosum are contributing to schizophrenia and cognition.

Published
2018
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25. Effects of the neurogranin variant rs12807809 on thalamocortical morphology in schizophrenia.

Author

Jamie Yu Jin Thong, Anqi Qiu, Min Yi Sum, Carissa Nadia Kuswanto, Ta Ahn Tuan, Gary Donohoe, Yih Yian Sitoh, and Kang Sim

Subjects
Medicine, Science
Abstract

Although the genome wide supported psychosis susceptibility neurogranin (NRGN) gene is expressed in human brains, it is unclear how it impacts brain morphology in schizophrenia. We investigated the influence of NRGN rs12807809 on cortical thickness, subcortical volumes and shapes in patients with schizophrenia. One hundred and fifty six subjects (91 patients with schizophrenia and 65 healthy controls) underwent structural MRI scans and their blood samples were genotyped. A brain mapping algorithm, large deformation diffeomorphic metric mapping, was used to perform group analysis of subcortical shapes and cortical thickness. Patients with risk TT genotype were associated with widespread cortical thinning involving frontal, parietal and temporal cortices compared with controls with TT genotype. No volumetric difference in subcortical structures (hippocampus, thalamus, amygdala, basal ganglia) was observed between risk TT genotype in patients and controls. However, patients with risk TT genotype were associated with thalamic shape abnormalities involving regions related to pulvinar and medial dorsal nuclei. Our results revealed the influence of the NRGN gene on thalamocortical morphology in schizophrenia involving widespread cortical thinning and thalamic shape abnormalities. These findings help to clarify underlying NRGN mediated pathophysiological mechanisms involving cortical-subcortical brain networks in schizophrenia.

Published
2013
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27. An evaluation of journalistic reporting on schizophrenia in the Irish news media

Author

Emmet Godfrey, Conor Gavin, Elaine Haskins, Áine O’Meara, Karen O’Connor, and Gary Donohoe

Subjects
Psychiatry and Mental health, History and Philosophy of Science, Applied Psychology
Abstract

Objectives: Schizophrenia represents one of the most stigmatised of mental disorders. Despite public awareness campaigns to raise awareness and increase understanding of mental health disorders, schizophrenia continues to be poorly understood. In this context, this study aims to provide a descriptive analysis of reporting on schizophrenia in the Irish online print news media. Methods: Online printed news articles which made reference to schizophrenia or related terms in 2021, the latest year for which full date was available, were collected. A list of criteria considered good reporting practise on mental illness in the media was curated. Additionally, a scale was developed based on these criteria to assign a valence to each article in terms of characteristics that were either stigma reinforcing or stigma challenging. Results: A total of 656 articles were included in the analysis. A majority of articles were found to avoid stigma reinforcing criteria (e.g. use of pejorative language). By contrast, few characteristics considered stigma challenging criteria were being endorsed (e.g. inclusion of a first person account). Overall sample valences show good reporting practises, but also suggested targets for improvement. Conclusions: While Irish online print news reports on schizophrenia and related illnesses avoid many stigmatising characteristics, many opportunities to challenge stigma remain.

Published
2023

28. Graph Convolutional Networks Reveal Network-Level Functional Dysconnectivity in Schizophrenia

Author

Du Lei, Kun Qin, Walter H L Pinaya, Jonathan Young, Therese Van Amelsvoort, Machteld Marcelis, Gary Donohoe, David O Mothersill, Aiden Corvin, Sandra Vieira, Su Lui, Cristina Scarpazza, Celso Arango, Ed Bullmore, Qiyong Gong, Philip McGuire, Andrea Mechelli, MUMC+: MA Med Staf Spec Psychiatrie (9), RS: MHeNs - R2 - Mental Health, Psychiatry 3, and Psychiatrie & Neuropsychologie

Subjects
Brain Mapping, OUTCOMES, Support Vector Machine, SYMPTOMS, neuroimaging, TOOLBOX, connectome, Brain, graph analysis, BRAIN NETWORKS, Psychiatry and Mental health, 1ST-EPISODE SCHIZOPHRENIA, DOPAMINE, PSYCHOSIS, machine learning, CONNECTIVITY, RELIABILITY, Schizophrenia, Humans, magnetic resonance imaging, psychosis
Abstract

Background and HypothesisSchizophrenia is increasingly understood as a disorder of brain dysconnectivity. Recently, graph-based approaches such as graph convolutional network (GCN) have been leveraged to explore complex pairwise similarities in imaging features among brain regions, which can reveal abstract and complex relationships within brain networks.Study DesignWe used GCN to investigate topological abnormalities of functional brain networks in schizophrenia. Resting-state functional magnetic resonance imaging data were acquired from 505 individuals with schizophrenia and 907 controls across 6 sites. Whole-brain functional connectivity matrix was extracted for each individual. We examined the performance of GCN relative to support vector machine (SVM), extracted the most salient regions contributing to both classification models, investigated the topological profiles of identified salient regions, and explored correlation between nodal topological properties of each salient region and severity of symptom.Study ResultsGCN enabled nominally higher classification accuracy (85.8%) compared with SVM (80.9%). Based on the saliency map, the most discriminative brain regions were located in a distributed network including striatal areas (ie, putamen, pallidum, and caudate) and the amygdala. Significant differences in the nodal efficiency of bilateral putamen and pallidum between patients and controls and its correlations with negative symptoms were detected in post hoc analysis.ConclusionsThe present study demonstrates that GCN allows classification of schizophrenia at the individual level with high accuracy, indicating a promising direction for detection of individual patients with schizophrenia. Functional topological deficits of striatal areas may represent a focal neural deficit of negative symptomatology in schizophrenia.

Published
2022

29. Measures of Social and Occupational Function in Early Psychosis: A Systematic Review and Meta-analysis

Author

Megan Cowman, Emmet Godfrey, Talissa Walsh, Emma Frawley, David Fowler, Mario Alvarez-Jimenez, Karen O’Connor, Til Wykes, Max Birchwood, and Gary Donohoe

Subjects
Psychiatry and Mental health
Abstract

Deficits in social and occupational function are widely reported in psychosis, yet no one measure of function is currently agreed upon as a gold standard in psychosis research. The aim of this study was to carry out a systematic review and meta-analysis of functioning measures to determine what measures were associated with largest effect sizes when measuring between-group differences, changes over time, or response to treatment. Literature searches were conducted based on PsycINFO and PubMed to identify studies for inclusion. Cross-sectional and longitudinal observational and intervention studies of early psychosis (≤5 years since diagnosis) that included social and occupational functioning as an outcome measure were considered. A series of meta-analyses were conducted to determine effect size differences for between-group differences, changes over time, or response to treatment. Subgroup analyses and meta-regression were carried out to account for variability in study and participant characteristics. One hundred and sixteen studies were included, 46 studies provided data (N = 13 261) relevant to our meta-analysis. Smallest effect sizes for changes in function over time and in response to treatment were observed for global measures, while more specific measures of social and occupational function showed the largest effect sizes. Differences in effect sizes between functioning measures remained significant after variability in study and participant characteristics were accounted for. Findings suggest that more specific measures of social function are better able to detect changes in function over time and in response to treatment.

Published
2023

31. Mendelian randomisation analysis using GWAS and eQTL data to investigate the relationship between chronotype and neuropsychiatric disorders and their molecular basis

Author

Shane Crinion, Cathy A. Wyse, Gary Donohoe, Lorna M. Lopez, and Derek W. Morris

Abstract

A wide range of comorbidities have been observed with neuropsychiatric disorders, of which sleep disturbances are one of the most common. Chronotype, a self-reported measurement of an individual’s preference for earlier or later sleep timing, is a proxy sleep measure that has been linked to neuropsychiatric disorders (NPDs). By investigating how chronotype influences risk for neuropsychiatric disorders and, vice versa, how risk for neuropsychiatric disorders influences chronotype, we may identify modifiable risk factors for each phenotype. By investigating the specific genetic mechanisms that are common to the risk of evening chronotype and the risk of NPDs, we may gain further understanding of the relationship and causal direction in these phenotypes. Here we use Mendelian randomisation (MR), a method used to explore causal effects, to 1) study the causal relationships between neuropsychiatric disorders and chronotype and 2) characterise the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between six neuropsychiatric disorders and chronotype using the largest genome-wide association studies (GWAS) available. Secondly, we integrated data from expression quantitative trait loci (eQTLs) to investigate the role of gene expression alterations on these phenotypes. We also used colocalization to validate that the same variant is causal for gene expression and each outcome. We identified that the evening chronotype is causal for increased risk of schizophrenia and autism spectrum disorder and, in the opposite direction, that insomnia and schizophrenia are causal for a tendency towards evening chronotype. We identified twelve eQTLs where gene expression changes in brain or blood were causal for one of the tested phenotypes (bipolar disorder, chronotype and schizophrenia). These findings provide important evidence for the complex, bidirectional relationship that exists between these sleep and neuropsychiatric disorders, and use gene expression data to identify causal roles for genes at associated loci.Author SummarySleep disturbances are commonly observed features of neuropsychiatric disorders. Chronotype, a behavioural manifestation of an individual’s preference for early or late sleep timing i.e. morning chronotype means a preference for earlier sleep and wake times, has been used as a behavioural marker of underlying circadian function. Here, we used data from the largest genetic studies available to test the causal relationship between chronotype and risk for neuropsychiatric disorders. We found that individuals with the evening chronotype have greater risk for schizophrenia or autism spectrum disorder. In the other direction, we found insomnia or schizophrenia diagnosis is causal for a tendency towards evening chronotype. We searched for DNA variants that influence chronotype or risk for neuropsychiatric disorders through alterations of gene expression in blood and brain tissues. We found twelve DNA variants with a significant effect on chronotype or risk of either bipolar disorder or schizophrenia. These results demonstrate that sleep and neuropsychiatric disorders have a complex bidirectional relationship and that the causal role of some genes is due to variants that alter gene expression.

Published
2023

32. Correction: Obesity and brain structure in schizophrenia – ENIGMA study in 3021 individuals

Author

Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, and Tomas Hajek

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Molecular Biology
Published
2023

35. Social and occupational recovery in early psychosis: a systematic review and meta-analysis of psychosocial interventions

Author

E Frawley, Gary Donohoe, Martin Lepage, and Megan Cowman

Subjects
Psychosis, business.industry, Psychological intervention, PsycINFO, medicine.disease, Psychiatry and Mental health, Cognitive remediation therapy, Meta-analysis, Intervention (counseling), medicine, business, Psychosocial, Applied Psychology, Supported employment, Clinical psychology
Abstract

BackgroundPsychosis, even in its early stages, ranks highly among the causes of disability worldwide, resulting in an increased focus on improved recovery of social and occupational functioning. This study aimed to provide an estimate of the effectiveness of psychosocial interventions for improving functioning in early psychosis. We also sought evidence of superiority between intervention approaches.MethodsAn electronic search was conducted using PubMed and PsycINFO to identify original articles reporting on trials of psychosocial interventions in early-stage psychosis, published up to December 2020 and is reported following PRISMA guidelines. Data were extracted on validated measures of functioning from included studies and pooled standardised mean difference (SMD) was estimated.ResultsIn total, 31 studies involving 2811 participants were included, focusing on: cognitive behavioural therapy for psychosis (CBTp), family-based therapy, supported employment, cognitive remediation training (CRT) and multi-component psychosocial interventions. Across interventions, improved function was observed (SMD = 0.239; 95% confidence interval 0.115–0.364, p < 0.001). Effect sizes varied by intervention type, stage of illness, length and duration of treatment and outcome measure used. In particular, interventions based on CRT significantly outperformed symptom-focused CBT interventions, while multi-component interventions were associated with largest gains.ConclusionsPsychosocial interventions, particularly when provided as part of a multi-component intervention model and delivered in community-based settings are associated with significant improvements in social and occupational function. This review underscores the value of sensitively tracking and targeting psychosocial function as part of the standard provided by early intervention services.

Published
2021

36. Associations between methylation age and brain age in late adolescence

Author

Faye Sanders, Vilte Baltramonaityte, Gary Donohoe, Neil M Davies, Erin C. Dunn, Charlotte A.M. Cecil, and Esther Walton

Abstract

Recent research suggests that biological age, based on DNA methylation or neuroimaging measures, may predict health traits in adulthood more accurately than chronological age. However, whether these findings apply to earlier stages in life is unknown. We therefore aimed to characterise the performance of and interdependence between measures of biological age during adolescence, leveraging longitudinal data from a subsample of young adolescents from the population-based ALSPAC cohort (n=386).We derived four methylation age measures in late adolescence (17-19 years) and a measure of brain age derived from structural neuroimaging data (18-24 years). We then examined associations between these measures of biological age, and their relationship with five measures of physical, cognitive and mental health (8-18 years).Brain age was largely independent of different measures of methylation age, even after accounting for age, cell type composition, array and study (beta range: -0.60 to 0.17, all p>0.05). Smoking and BMI predicted three measures of advanced methylation age (beta range: -0.39 to 0.52, all pOur findings emphasize the variability of and independence between these methylation- and brain-based measures of age in adolescents. They also highlight the importance of tracking the mosaic of ageing in younger populations.

Published
2022

37. Corrigendum to ’Childhood trauma is associated with altered white matter microstructural organization in schizophrenia’ Psychiatry Research: Neuroimaging, 330 (2023) 111616

Author

Laura Costello, Maria R. Dauvermann, Giulia Tronchin, Laurena Holleran, David Mothersill, Karolina I. Rokita, Ruán Kane, Brian Hallahan, Aiden Corvin, Derek Morris, Declan P. McKernan, John Kelly, Colm McDonald, Gary Donohoe, and Dara M. Cannon

Subjects
Psychiatry and Mental health, Neuroscience (miscellaneous), Radiology, Nuclear Medicine and imaging
Published
2023

38. The relationship between inflammatory biomarkers and cognitive dysfunction in patients with schizophrenia: A systematic review and meta-analysis

Author

Saahithh Redddi Patlola, Gary Donohoe, and Declan P. McKernan

Subjects
Pharmacology, Inflammation, C-Reactive Protein, Interleukin-6, Tumor Necrosis Factor-alpha, Schizophrenia, Quality of Life, Humans, Cognitive Dysfunction, Biological Psychiatry, Biomarkers
Abstract

Schizophrenia is a complex psychiatric disorder that includes positive and negative symptoms but also debilitating cognitive deficits. Current pharmacological interventions do not target these deficits. Recent evidence suggests a connection between some inflammatory markers (including C-reactive protein) and cognitive impairment, but did not address other inflammatory markers. In the current study, we try to fill the gap by focusing on the association of Interleukin-6 (IL-6), IL-1β, Tumor Necrosis Factor-α and CRP with cognitive dysfunction.PUBMED and Web of Science databases were searched for all studies published until July 2022. A total of 25 studies were included in an analysis of the association between cognitive performance and variation in IL-6, IL-1β, TNF-α and CRP.A total of 2398 patients were included in this study. Meta-analyses results showed a significant inverse relationship between performance in five cognitive domains (attention-processing speed, executive function, working memory, verbal and visual learning and memory) and systemic IL-6, IL-1β, TNF-α and CRP plasma levels in patients with schizophrenia. The meta-analyses results showed a significant decline in the cognitive performances with the evaluated inflammatory markers with effect sizes ranging from -0.136 to -0.181 for IL-6, -0.188 to -0.38 for TNF-α -0.372 to -0.476 for IL-1β and - 0.168 to -0.311 for CRP.Findings from the current study shows that cognitive deficits are reflective of elevated proinflammatory biomarkers (IL-6, IL-1β, TNF-α and CRP) levels. The results obtained indicate relatedness between inflammation and cognitive decline in patients with schizophrenia. Understanding the underlying pathways between them could have a significant impact on the disease progression and quality of life in schizophrenia patients.

Published
2022

39. Systematic Review and Meta-Analysis of Damage Associated Molecular Patterns HMGB1 and S100B in Schizophrenia

Author

Michael Mackey, Laurena Holleran, Gary Donohoe, and Declan P. McKernan

Subjects
Psychiatry and Mental health, Biological Psychiatry
Abstract

Objective Immune system dysregulation is hypothesised to be central to the aetiopathogenesis of schizophrenia; however, the role of sterile inflammation remains unclear. Damage associated molecular patterns are key initiators of sterile inflammation and are detectable in peripheral blood.Methods A defined systematic search of the Web of Science, PubMed, and Scopus was performed to identify adult case-control studies published between January 1990 and June 2022. Three studies consisting of 242 cases and 83 controls met inclusion for the systematic review and meta-analysis of HMGB1 while twenty-eight studies consisting of 1,544 cases and 1,248 healthy controls were included for S100B.Results A significant standardised mean difference in peripheral S100B and HMGB1 concentrations was detected between cases and controls. S100B subgroup analysis determined the largest significant effect size for unmedicated individuals diagnosed with schizophrenia.Conclusion This study provides evidence that peripheral S100B and HMGB1 concentrations are elevated in individuals diagnosed with schizophrenia when compared with healthy controls. These results should be interpreted with caution as significant heterogeneity was present during meta-analysis of S100B in the entire sample and in sub-group analysis. The persistence of significant heterogeneity throughout subgroup analysis indicates that the current diagnostic groupings may be a barrier to understanding human behaviours and emotions.

Published
2022

40. Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals

Author

Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, Tomas Hajek, European Commission, European Research Council, German Research Foundation, Agencia Nacional de Investigación y Desarrollo (Chile), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), and Alexander von Humboldt Foundation

Subjects
Medical and Health Sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Clinical Research, 2.1 Biological and endogenous factors, Humans, Obesity, Aetiology, Molecular Biology, Nutrition, Psychiatry, Depressive Disorder, Depressive Disorder, Major, Psychology and Cognitive Sciences, Neurosciences, Major, Brain, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Biomedical Imaging
Abstract

Hajek, Tomas: et al., Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia., NAC et al. were supported by the Agencia Nacional de Investigación y Desarrollo, Chile, through its grants PIA ACT1414, ANID-PIA-ACT 192064, and FONDECYT regular 1200601. This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). The NUDZ and IKEM sites were supported by funding from the Ministry of Health of the Czech Republic (16-32791A, NU20-04-00393) and conceptual development of research organization (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001). This work was also funded by the German Research Foundation (DFG grant FOR2107, KI588/14-1 and FOR2107, KI588/14-2 to TTJK, Marburg, Germany), as well as, the Alexander von Humboldt Foundation, EU and Deutsche Forschungsgemeinschaft (DFG), grants NE2254/1-2, NE2254/3-1, NE2254/4-1. Additional support provided by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/05028), and the Singapore Bioimaging Consortium (RP C009/2006) research grants awarded to KS. EW was supported by the European Union’s Horizon 2020 research and innovation programme (Early Cause, grant n° 848158). Funding for TWW was provided by the National Health and Medical Research Council Australia Project Grant 568807; New South Wales Health, University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute. GD’s research was funded by the European Research Council 677467 and Science Foundation Ireland 16/ERCS/3787. VDC was supported by NIH R01MH118695. PMT was supported by NIMH grant R01MH116147. Lastly, TH was supported by funding from the Canadian Institutes of Health Research (103703, 106469 and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to TH.

Published
2022

41. The Impact of Early Adversity and Educational Attainment on Genetic and Brain Morphological Predictors of Intelligence

Author

Gary Donohoe, Emma Corley, Laura Fahey, Joan Fitzgerald, Laurena Holleran, Esther Walton, and Derek Morris

Subjects
Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Biological Psychiatry
Abstract

Intelligence is a strong predictor of occupational achievement, quality of life and physical health. While variation in intelligence is strongly heritable and has been robustly associated with early environment and brain morphology, little is known about how these factors combine and interact to explain this variation in intelligence. To address this, we modelled the relationship between common genetic variation, grey matter volume, early life adversity and education and intelligence in a UK Biobank sample of 16,383 individuals using structural equation modelling. We tested the hypotheses that total grey matter volume would mediate the association between genetics and intelligence, and that early life adversity and educational attainment would moderate this relationship. Common genetic variation was estimated using a genome-wide polygenic score (PGS) of intelligence. Consistent with previous studies, we found that grey matter volume was a significant mediator of the relationship between PGS and intelligence, but only when early life adversity was included in the model. We further found that higher educational attainment in turn moderated the effects of adversity. These findings suggest an important interaction between genetic and environmental factors in the development of intellectual functioning.

Published
2022

42. Cognitive Predictors of Social and Occupational Functioning in Early Psychosis: A Systematic Review and Meta-analysis of Cross-Sectional and Longitudinal Data

Author

Karen O'Connor, Edgar Lonergan, Megan Cowman, Gary Donohoe, Laurena Holleran, and Max Birchwood

Subjects
early psychosis, cognition, Employment, Social Cognition, AcademicSubjects/MED00810, BF, PsycINFO, 03 medical and health sciences, 0302 clinical medicine, Social cognition, medicine, Humans, Cognitive Dysfunction, Effects of sleep deprivation on cognitive performance, Longitudinal Studies, Early psychosis, occupational function, Cognition, medicine.disease, 030227 psychiatry, schizophrenia, Psychiatry and Mental health, Psychosocial Functioning, Cross-Sectional Studies, Psychotic Disorders, Schizophrenia, Meta-analysis, social function, Psychology, 030217 neurology & neurosurgery, Social cognitive theory, RC, Clinical psychology, Regular Articles
Abstract

Many individuals with early psychosis experience impairments in social and occupational function. Identification of modifiable predictors of function such as cognitive performance has the potential to inform effective treatments. Our aim was to estimate the strength of the relationship between psychosocial function in early psychosis and different domains of cognitive and social cognitive performance. We conducted a systematic review and meta-analysis of peer-reviewed, cross-sectional, and longitudinal studies examining cognitive predictors of psychosocial function. Literature searches were conducted in PsycINFO, PubMed, and reference lists of relevant articles to identify studies for inclusion. Of the 2565 identified, 46 studies comprising 3767 participants met inclusion criteria. Separate meta-analyses were conducted for 9 cognitive domains. Pearson correlation values between cognitive variables and function were extracted. All cognitive domains were related to psychosocial function both cross-sectionally and longitudinally. Importantly, these associations remained significant even after the effects of symptom severity, duration of untreated psychosis, and length of illness were accounted for. Overall, general cognitive ability and social cognition were most strongly associated with both concurrent and long-term function. Associations demonstrated medium effect sizes. These findings suggest that treatments targeting cognitive deficits, in particular those focusing on social cognition, are likely to be important for improving functional outcomes in early psychosis. [Abstract copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.]

Published
2021

44. Brain charts for the human lifespan

Author

Armin Raznahan, Eric Courchesne, Andrea Parolin Jackowski, Kamen A. Tsvetanov, Cameron T. Ellis, R.C. Gur, Bin Bae J, Park Mtm, Pedro A. Valdes-Sosa, Simon N. Vandekar, Jacob W. Vogel, Juan Zhou, Machteld Marcelis, Kiho Im, Patricia Ellen Grant, Minhui Ouyang, Blesa Cabez M, Michael V. Lombardo, Sarah E. Morgan, James P. Boardman, Adamson C, Calhoun Vd, Delarue M, James H. Cole, Pichet Binette A, Roberto Toro, David H. Rowitch, Nynke A. Groenewold, Kevin M. Anderson, David T.W. Jones, Michael Schöll, Wang Ys, Aiden Corvin, R.E. Gur, Damien A. Fair, Gareth Ball, Herma Lina Schaare, Andrew Zalesky, Evdokia Anagnostou, Michael J. Meaney, Taki Y, Gareth J. Sullivan, Warrier, Petra E. Vértes, Chixiang Chen, Lisa T. Eyler, Wei Liao, Tomáš Paus, Jeremy A. Elman, Phillip McGuire, Hisham Ziauddeen, William S. Kremen, Etienne Vachon-Presseau, E.T. Bullmore, Christophe Tzourio, White, Hammill Cf, Mothersill D, Richard N. Henson, Jiang Qiu, Duncan E. Astle, Fabrice Crivello, Paul C. Fletcher, Chertavian C, Kim K, Jennifer Crosbie, Russell Schachar, Gabriel A. Devenyi, Manfred G. Kitzbichler, Tianye Jia, Trey Hedden, Sang Jae Lee, Ross D. Markello, Silke Kern, Ian M. Goodyer, Keith A. Johnson, Frauke Beyer, Bernard Mazoyer, A. Heinz, Sylvane Desrivières, Rosenberg, Gary Donohoe, Ong Mq, Alexander D. Edwards, Dan J. Stein, Nenad Medic, Zuo Xn, Travis T. Mallard, Peter Fonagy, Lindsay W. Victoria, Ingmar Skoog, Avram J. Holmes, Jason P. Lerch, Jed T. Elison, Jianfu Li, John H. Gilmore, Rosemary Holt, Caitlin K. Rollins, Carol E. Franz, Pedro Mario Pan, Saashi A Bedford, Yang N, Jonathan C Ipser, Richard A. I. Bethlehem, Tuulari Jj, Stolicyn A, Hua Huang, Bratislav Misic, Conor Liston, Ayub M, Lisa Ronan, Yeo Bt, Sophie Adler, Charles J. Lynch, Faith M. Gunning, Konrad Wagstyl, M. Mallar Chakravarty, John Suckling, Theodore D. Satterthwaite, Bharath Holla, Yap Seng Chong, Jinglei Lv, Jakob Seidlitz, Niall J Bourke, Xinlei Qian, Simon Baron-Cohen, Cynthia M. Ortinau, Deirel Paz Linares, Thyreau B, René S. Kahn, Aaron P. Schultz, Vanessa Cropley, Eric Westman, Mitchell Valdés-Sosa, Rik Ossenkoppele, André Zugman, Hasse Karlsson, Sylvia Villeneuve, Katja Heuer, Di Biase Ma, Margaret L. Westwater, Sofie L. Valk, David J. Sharp, Brigitte Landeau, Matthew Borzage, Kirsten A. Donald, Timothy Rittman, Richard Beare, Giovanni Abrahão Salum, Gunter Schumann, Ryuta Kawashima, Romero-Garcia R, John Blangero, Yun Hj, Russel T. Shinohara, Nicolas Crossley, Simon K. Warfield, Karen Pierce, George S. Alexopoulos, Katharine Dunlop, David C. Glahn, Francois Lalonde, Anqi Qiu, Lana Vasung, Gaël Chételat, Lídice Galán-García, Clifford R. Jack, Reisa A. Sperling, Anna Zettergren, Elizabeth Kelley, Arno Villringer, Andrea Mechelli, Benegal, Aaron Alexander-Bloch, Nicholas B. Turk-Browne, van Amelsvoort T, John D. Lewis, Heather C. Whalley, A. V. Witte, Zdenka Pausova, Joel T. Nigg, Heather J. Zar, Raymond J. Dolan, Christopher D. Smyser, Jay N. Giedd, Lena Palaniyappan, Ali Gholipour, Areces-Gonzalez A, Peter B. Jones, Jacqueline Hoare, Oskar Hansson, Linnea Karlsson, C Pantelis, Paly L, Bonnie Auyeung, Jorge Bosch-Bayard, Bethlehem, Richard [0000-0002-0714-0685], White, Simon [0000-0001-8642-7037], Astle, Duncan [0000-0002-7042-5392], Baron-Cohen, Simon [0000-0001-9217-2544], Henson, Rik [0000-0002-0712-2639], Jones, Peter [0000-0002-0387-880X], Kitzbichler, Manfred [0000-0002-4494-0753], Rittman, Timothy [0000-0003-1063-6937], Rowitch, David [0000-0002-0079-0060], Tsvetanov, Kamen A. [0000-0002-3178-6363], Westwater-Wozniak, Margaret [0000-0002-2918-0979], Ziauddeen, Hisham [0000-0003-4044-1719], Apollo - University of Cambridge Repository, British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, University of Cambridge [UK] (CAM), University of Pennsylvania, Yale University [New Haven], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neuroscience - Department of Neuroscience, Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Neurology, Amsterdam Neuroscience - Neurodegeneration, 3R-BRAIN, AIBL, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Repository Without Borders Investigators, CALM Team, Cam-CAN, CCNP, COBRE, cVEDA, ENIGMA Developmental Brain Age Working Group, Developing Human Connectome Project, FinnBrain, Harvard Aging Brain Study, IMAGEN, KNE96, The Mayo Clinic Study of Aging, NSPN, POND, The PREVENT-AD Research Group, VETSA, [Bethlehem, R. 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V.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Blangero, J.] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Dept Human Genet, Edinburg, TX USA, [Blesa Cabez, M.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Boardman, J. P.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Sullivan, G.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Borzage, M.] Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Fetal & Neonatal Inst,Div Neonatol,Dept Pediat, Los Angeles, CA 90007 USA, [Bosch-Bayard, J. F.] Montreal Neurol Inst, Ludmer Ctr Neuroinformat & Mental Hlth, McGill Ctr Integrat Neurosci, Montreal, PQ, Canada, [Bosch-Bayard, J. F.] McGill Univ, Montreal, PQ, Canada, [Chakravarty, M. 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J.] Yale Univ, Dept Psychol, New Haven, CT USA, [Villeneuve, S.] Yale Univ, Dept Psychol, New Haven, CT USA, [Holmes, A. J.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Villeneuve, S.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Huang, H.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Ouyang, M.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Huang, H.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA, [Ipser, J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Clin Neurosci Inst, Cape Town, South Africa, [Jack, C. R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA, [Jones, D. T.] Mayo Clin, Dept Radiol, Rochester, MN USA, Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil, [Jackowski, A. 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A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA, [Jones, D. T.] Mayo Clin, Dept Neurol, Rochester, MN USA, [3R-BRAIN] Mayo Clin, Dept Neurol, Rochester, MN USA, [Kahn, R. S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA, [Karlsson, H.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, L.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, H.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, L.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Tuulari, J. J.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Turku, Finland, [Tuulari, J. J.] Turku Univ Hosp, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, H.] Univ Turku, Turku, Finland, [Karlsson, L.] Univ Turku, Turku, Finland, [Kawashima, R.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Taki, Y.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Thyreau, B.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychol, Kingston, ON, Canada, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychiat, Kingston, ON, Canada, [Kern, S.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Skoog, I.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Zettergren, A.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Kern, S.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Skoog, I.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Kim, K. W.] Seoul Natl Univ, Dept Brain & Cognit Sci, Coll Nat Sci, Seoul, South Korea, [Kim, K. W.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Kim, K. W.] Seoul Natl Univ, Dept Psychiat, Coll Med, Seoul, South Korea, [Kim, K. W.] SNU MRC, Inst Human Behav Med, Seoul, South Korea, [Lalonde, F.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Raznahan, A.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Lee, S.] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul, South Korea, [Lerch, J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada, [Lerch, J.] Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB, Wellcome Ctr Integrat Neuroimaging, Oxford, England, [Lewis, J. D.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada, [Li, J.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liao, W.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Valdes-Sosa, P. A.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liston, C.] Weill Cornell Med, Dept Psychiat, New York, NY USA, [Liston, C.] Weill Cornell Med, Brain & Mind Res Inst, New York, NY USA, [Lombardo, M. V.] Ist Italiano Tecnol, Ctr Neurosci & Cognit Syst UniTn, Lab Autism & Neurodev Disorders, Rovereto, Italy, [Lv, J.] Univ Sydney, Sch Biomed Engn, Sydney, NSW, Australia, [Lv, J.] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia, [Mallard, T. T.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA, [Marcelis, M.] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, EURON,Med Ctr, Maastricht, Netherlands, [Marcelis, M.] Inst Mental Hlth Care Eindhoven GGzE, Eindhoven, Netherlands, [Markello, R. D.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Misic, B.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Vasung, L.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Mazoyer, B.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Singapore Inst Clin Sci, Singapore, Singapore, [Mechelli, A.] Bordeaux Univ Hosp, Bordeaux, France, [Morgan, S. E.] Univ Cambridge, Dept Comp Sci & Technol, Cambridge, England, [Morgan, S. E.] Alan Turing Inst, London, England, [Vertes, P. E.] Alan Turing Inst, London, England, [Mothersill, D.] Natl Coll Ireland, Sch Business, Dept Psychol, Dublin, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Sch Psychol, Galway, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom, Galway, Ireland, [Mothersill, D.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland, [Nigg, J.] Oregon Hlth & Sci Univ, Dept Psychiat, Sch Med, Portland, OR 97201 USA, [Ong, M. Q. W.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Qian, X.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Ortinau, C.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA, [Ossenkoppele, R.] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC, Dept Neurol,Amsterdam Neurosci, Amsterdam, Netherlands, [Ossenkoppele, R.] Lund Univ, Clin Memory Res Unit, Lund, Sweden, [Palaniyappan, L.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada, [Palaniyappan, L.] Univ Western Ontario, Brain & Mind Inst, London, ON, Canada, [Pan, P. M.] Fed Univ Sao Poalo UNIFESP, Dept Psychiat, Sao Poalo, Brazil, [Pan, P. M.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Zugman, A.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Pantelis, C.] Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia, [Pantelis, C.] Melbourne Hlth, Carlton, Vic, Australia, [Pantelis, C.] Univ Melbourne, Melbourne Sch Engn, Parkville, Vic, Australia, [Pantelis, C.] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia, [Park, M. M.] Western Univ, Schulich Sch Med & Dent, Dept Psychiat, London, ON, Canada, [Rollins, C. K.] Univ Montreal, Dept Psychiat, Fac Med, Montreal, PQ, Canada, [Rollins, C. K.] Univ Montreal, CHU St Justine, Montreal, PQ, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Physiol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada, [Paz-Linares, D.] Cuban Neurosci Ctr, Havana, Cuba, [Pichet Binette, A.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Villeneuve, S.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Pichet Binette, A.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Villeneuve, S.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Qiu, J.] Southwest Univ, Sch Psychol, Chongqing, Peoples R China, [Qiu, A.] Natl Univ Singapore, N1 Inst Hlth, Dept Biomed Engn, Singapore, Singapore, [Rittman, T.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Tsvetanov, K. A.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Rollins, C. K.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA, [Rollins, C. K.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA, [Romero-Garcia, R.] Univ Seville, Dpto Fisiol Med & Biofis, Inst Biomed Sevilla IBiS HUVR CSIC, Seville, Spain, [Rosenberg, M. D.] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA, [Rosenberg, M. D.] Univ Chicago, Inst Neurosci, Chicago, IL USA, [Rowitch, D. H.] Univ Cambridge, Dept Paediat, Cambridge, England, [Rowitch, D. H.] Univ Cambridge, Wellcome MRC Cambridge Stem Cell Inst, Cambridge, England, [Salum, G. A.] Univ Fed Rio Grande Sul UFRGS, Hosp Clin Porto Alegre, Dept Psychiat, Porto Alegre, RS, Brazil, [Salum, G. A.] Natl Inst Dev Psychiat INPD, Sao Paulo, Brazil, [Schaare, H. L.] Max Planck Inst Human Cognit & Brain Sci, Otto Hahn Grp Cognit Neurogenet, Leipzig, Germany, [Schaare, H. L.] Res Ctr Juelich, Inst Neurosci & Med INM 7 Brain & Behav, Julich, Germany, [Schultz, A. P.] Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA, [Schumann, G.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Ctr Populat Neurosci & Stratified Med PONS, Shanghai, Peoples R China, [Schumann, G.] Charite Campus Mitte, Dept Psychiat & Psychotherapy, Charite Mental Hlth, PONS Ctr, Berlin, Germany, [Scholl, M.] Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden, [Scholl, M.] Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden, [Scholl, M.] UCL, Queens Sq Inst Neurol, Dementia Res Ctr, London, England, [Sharp, D.] UK Dementia Res Inst, Care Res & Technol Ctr, London, England, [Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA, [Stein, D. J.] Univ Cape Town, Dept Psychiat, SA MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa, [Stein, D. J.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Stolicyn, A.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Whalley, H. C.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Toro, R.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Univ Paris 05, Ctr Res & Interdisciplinar CRI, Paris, France, [Tsvetanov, K. A.] Univ Cambridge, Dept Psychol, Cambridge, England, [Turk-Browne, N. B.] Yale Univ, Wu Tsai Inst, New Haven, CT USA, [Tuulari, J. J.] Univ Turku, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Turku Coll Sci Med & Technol, Turku, Finland, [Tzourio, C.] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux, U1219,INSERM, Bordeaux, France, [Vachon-Presseau, E.] McGill Univ, Fac Dent Med & Oral Hlth Sci, Montreal, PQ, Canada, [Valdes-Sosa, P. A.] McGill Univ, Alan Edwards Ctr Res Pain AECRP, Montreal, PQ, Canada, [Valk, S. L.] Forschungszentrum Julich, Inst Neurosci & Med 7, Julich, Germany, [Valk, S. L.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany, [van Amelsvoort, T.] Maastricht Univ, Dept Psychiat & Neurosychol, Maastricht, Netherlands, [Vandekar, S. N.] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA, [Villeneuve, S.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA, [Villringer, A.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Witte, A. V.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Zuo, X. N.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Wang, Y. S.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yeo, B.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Wang, Y. S.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Wang, Y. S.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Yang, N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Zuo, X. N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Wang, Y. S.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Yang, N.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Westman, E.] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden, [Witte, A. V.] Univ Leipzig, CRC 1052 Obes Mech, Fac Med, Leipzig, Germany, [Zhou, J. H.] Natl Univ Singapore, Dept Elect & Comp Engn, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat MR Res, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, N1 Inst Hlth, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Inst Digital Med, Singapore, Singapore, [Yun, H.] Natl Univ Singapore, Integrat Sci & Engn Programme ISEP, Singapore, Singapore, [Zar, H. J.] Univ Melbourne, Dept Biomed Engn, Melbourne, Vic, Australia, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat Magnet Resonance Res, Singapore, Singapore, [Ziauddeen, H.] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Cambridge, England, [Zugman, A.] NIMH, NIH, Bethesda, MD 20892 USA, [Zugman, A.] Escola Paulista Med, Dept Psychiat, Sao Paulo, Brazil, [Zuo, X. N.] Nanning Normal Univ, Sch Educ Sci, Key Lab Brain & Educ, Nanning, Peoples R China, British Academy Postdoctoral fellowship, NIMH, UKRI Medical Research Council, NIHR Cambridge Biomedical Research Centre, NIHR Senior Investigator award, MRC research infrastructure award, Commonwealth Scientific and Industrial Research Organisation (CSIRO), and Ontario Brain Institute

Subjects
631/378/2649, OpenPain Project, KNE96, Growth, Psychiatric-disorders, DISEASE, 3R-BRAIN, Brain charts, MRI Brain, OASIS-3, Disease, CCNP, 631/378/2571, UMN BCP, Multidisciplinary, medicine.diagnostic_test, PSYCHIATRIC-DISORDERS, article, Brain, Human brain, ASSOCIATION, Magnetic Resonance Imaging, Harvard Aging Brain Study, The Mayo Clinic Study of Aging, NSPN, medicine.anatomical_structure, GROWTH, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:500, BURDEN, WHITE-MATTER, FinnBrain, Harvard Aging Brain Study, Organization, Mri, MRI, medicine.medical_specialty, Concurrent validity, MODELS, Cam-CAN, Longevity, CALM Team, POND, Neuroimaging, Burden, ORGANIZATION, AIBL, The PREVENT-AD Research Group, VETSA, Cortical thickness, Association, Physical medicine and rehabilitation, FinnBrain, IMAGEN, KNE96, White-matter, medicine, Humans, ASRB, 631/378/1689, COBRE, business.industry, 631/378/2611, Brain morphometry, Neurosciences, Alzheimer’s Disease Repository Without Borders Investigators, Magnetic resonance imaging, Alzheimer’s Disease Neuroimaging Initiative, Anthropometry, Body Height, Brain growth, Birth, 59/57, Normative, IMAGEN, ENIGMA Developmental Brain Age working group, NSPN, business, CCNP, 3R-BRAIN, CORTICAL THICKNESS, Developing Human Connectome Project, ENIGMA Developmental Brain Age working group, The PREVENT-AD Research Group, VETSA, Bullmore, E.T
Abstract

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Published
2022

45. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Author

Bruce Pike, Masaki Fukunaga, Erik G. Jönsson, Robin M. Murray, Abdel Abdellaoui, Christopher R.K. Ching, Simon E. Fisher, Henry Brodaty, James Rucker, Gary Donohoe, Robin Bülow, Greig I. de Zubicaray, Stefan Johansson, Katrin Amunts, Katharina Wittfeld, Arvid Lundervold, Vincent Frouin, Ida E Sønderby, Tetyana Zayats, Carlos Prieto, Vince D. Calhoun, Anders M. Dale, Hilleke E. Hulshoff Pol, Tomáš Paus, Lars Nyberg, David C. Glahn, Benedicto Crespo-Facorro, Nicholas B. Blackburn, Gunter Schumann, Thomas Espeseth, Lars T. Westlye, Loes M. Olde Loohuis, Dan J. Stein, Dorret I. Boomsma, Dennis van der Meer, Stefan Ehrlich, Stephanie Le Hellard, Elena Shumskaya, Tiago Reis Marques, Manon Bernard, Nicholas G. Martin, Jan Haavik, Rachel M. Brouwer, Simone Ciufolini, Marta Di Forti, Shareefa Dalvie, Perminder S. Sachdev, Oleksandr Frei, Emma Knowles, Samuel R. Mathias, Else Eising, Ingrid Agartz, Clara Moreau, Nicola J. Armstrong, Dennis van 't Ent, Norman Delanty, Christian K. Tamnes, Evangelos Vassos, Marianne Bernadette van den Bree, Christiane Jockwitz, Magnus O. Ulfarsson, Katie L. McMahon, Allan F. McRae, Thomas W. Mühleisen, Peter R. Schofield, Sarah E. Medland, Hreinn Stefansson, David Edmund Johannes Linden, Céline S. Reinbold, Sanjay M. Sisodiya, Wei Wen, Paul M. Thompson, Jouke-Jan Hottenga, Paola Dazzan, Kari Stefansson, Alexander Teumer, Eco J. C. de Geus, Per Hoffmann, Neda Jahanshad, Jingyu Liu, Joanne E. Curran, Juan M. Peralta, Laurena Holleran, Ana I. Silva, Asta Håberg, Thomas Gareau, Karen A. Mather, Srdjan Djurovic, Lachlan T. Strike, Anbupalam Thalamuthu, Hans J. Grabe, Ryota Hashimoto, Tormod Fladby, Manon H.J. Hillegers, Tobias Kaufmann, Masataka Kikuchi, Jan Egil Nordvik, Zdenka Pausova, Omar Gustafsson, Gianpiero L. Cavalleri, Margaret J. Wright, Nynke A. Groenewold, Wiepke Cahn, Astri J. Lundervold, Michael John Owen, Diana Tordesillas-Gutiérrez, Sven Cichon, Sonja M C de Zwarte, Torgeir Moberget, Vidar M. Steen, John Blangero, Derek W. Morris, Roel A. Ophoff, Derrek P. Hibar, Andrew J. Schork, Anouk den Braber, Jayne Y. Hehir-Kwa, G. Bragi Walters, Micael Andersson, Sigrid Botne Sando, Joanne L. Doherty, Aiden Corvin, Sébastien Jacquemont, Erin Burke Quinlan, John B.J. Kwok, Anne Uhlmann, David Ames, Jean Shin, Svenja Caspers, Sylvane Desrivières, Ole A. Andreassen, Masashi Ikeda, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biological Psychology, Stochastics, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, National Institutes of Health (US), European Commission, Research Council of Norway, University of Oslo, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, and RS: MHeNs - R3 - Neuroscience

Subjects
Netherlands Twin Register (NTR), Male, Oncology, Translation, Duplication, Genome-wide association study, physiology [DNA Copy Number Variations], Neuropsychological Tests, Language in Interaction, Chromosome Breakpoints, Cognition, genetics [Chromosomes, Human, Pair 15], diagnostic imaging [Cerebral Cortex], Copy-number variation, Original Investigation, Cerebral Cortex, education.field_of_study, Connectivity, Organ Size, Middle Aged, Magnetic Resonance Imaging, Psychiatry and Mental health, DROSOPHILA, anatomy & histology [Cerebral Cortex], Brain size, Female, Neuroinformatics, Heterozygote, medicine.medical_specialty, CORTEX, GENES, MICRODUPLICATION, DNA Copy Number Variations, genetics [DNA Copy Number Variations], Population, Neuroimaging, SURFACE-AREA, Biology, Structural variation, physiology [Cerebral Cortex], Internal medicine, Neuroplasticity, THICKNESS, medicine, Humans, ddc:610, education, Genetic Association Studies, Genetic association, Chromosomes, Human, Pair 15, genetics [Organ Size], Brain morphometry, Brain Cortical Thickness, Microdeletion
Abstract

ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bulow, Robin; Cahn, Wiepke; Calhoun, Vince D; Caspers, Svenja; Cavalleri, Gianpiero L; Ching, Christopher R K; Cichon, Sven; Ciufolini, Simone; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Dalvie, Shareefa; Dazzan, Paola; de Geus, Eco J C; de Zubicaray, Greig I; de Zwarte, Sonja M C; Delanty, Norman; den Braber, Anouk; Desrivieres, Sylvane; Di Forti, Marta; Doherty, Joanne L; Donohoe, Gary; Ehrlich, Stefan; Eising, Else; Espeseth, Thomas; Fisher, Simon E; Fladby, Tormod; Frei, Oleksandr; Frouin, Vincent; Fukunaga, Masaki; Gareau, Thomas; Glahn, David C; Grabe, Hans J; Groenewold, Nynke A; Gustafsson, Omar; Haavik, Jan; Haberg, Asta K; Hashimoto, Ryota; Hehir-Kwa, Jayne Y; Hibar, Derrek P; Hillegers, Manon H J; Hoffmann, Per; Holleran, Laurena; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jacquemont, Sebastien; Jahanshad, Neda; Jockwitz, Christiane; Johansson, Stefan; Jonsson, Erik G; Kikuchi, Masataka; Knowles, Emma E M; Kwok, John B; Le Hellard, Stephanie; Linden, David E J; Liu, Jingyu; Lundervold, Arvid; Lundervold, Astri J; Martin, Nicholas G; Mather, Karen A; Mathias, Samuel R; McMahon, Katie L; McRae, Allan F; Medland, Sarah E; Moberget, Torgeir; Moreau, Clara; Morris, Derek W; Muhleisen, Thomas W; Murray, Robin M; Nordvik, Jan E; Nyberg, Lars; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Michael J; Paus, Tomas; Pausova, Zdenka; Peralta, Juan M; Pike, Bruce; Prieto, Carlos; Quinlan, Erin Burke; Reinbold, Celine S; Reis Marques, Tiago; Rucker, James J H; Sachdev, Perminder S; Sando, Sigrid B; Schofield, Peter R; Schork, Andrew J; Schumann, Gunter; Shin, Jean; Shumskaya, Elena; Silva, Ana I; Sisodiya, Sanjay M; Steen, Vidar M; Stein, Dan J; Strike, Lachlan T; Tamnes, Christian K; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutierrez, Diana; Uhlmann, Anne; Ulfarsson, Magnus O; van 't Ent, Dennis; van den Bree, Marianne B M; Vassos, Evangelos; Wen, Wei; Wittfeld, Katharina; Wright, Margaret J; Zayats, Tetyana; Dale, Anders M; Djurovic, Srdjan; Agartz, Ingrid; Westlye, Lars T; Stefansson, Hreinn; Stefansson, Kari; Thompson, Paul M; Andreassen, Ole A., [Importance] Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., [Objective] To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., [Design, Setting, and Participants] In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., [Main Outcomes and Measures] The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., [Results] Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., [Conclusions and Relevance] These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders., This study is supported in part by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Groupand owned by the University of Oslo.

Published
2020

46. Effects of early life adversity on immune function and cognitive performance: results from the ALSPAC cohort

Author

Jessica Holland, Maria R. Dauvermann, Stanley Zammit, Gary Donohoe, Derek W. Morris, and Gulam Khandaker

Subjects
Adult, Male, Longitudinal study, Health (social science), Adolescent, Social Psychology, Epidemiology, Theory of Mind, Adversity, Young Adult, 03 medical and health sciences, Cognition, 0302 clinical medicine, 5. Gender equality, Adverse Childhood Experiences, Risk Factors, Social cognition, Theory of mind, Humans, Longitudinal Studies, 030212 general & internal medicine, Effects of sleep deprivation on cognitive performance, Immune response, Child, Psychological abuse, Inflammation, Intelligence quotient, Interleukin-6, Mental Disorders, ALSPAC, 16. Peace & justice, Mental health, United Kingdom, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, C-Reactive Protein, Child, Preschool, Female, Psychology, Biomarkers, Clinical psychology
Abstract

Background\ud Early life adversity (ELA) is a significant risk factor for mental health disorders. One hypothesised mechanism by which this occurs is via an effect on immune response. In this analysis of epidemiological data, we tested whether ELA was associated with cognitive performance, and if so, whether these effects were influenced by immune function.\ud Methods\ud We investigated the longitudinal relationship between ELA, inflammatory markers, and cognition in data from Avon Longitudinal Study of Parents And Children (ALSPAC; n ~ 5000). ELA was defined in terms of physical/emotional abuse, harsh parenting, or domestic violence before 5 years. Social cognition was measured in terms of theory of mind, and general cognitive ability was measured using IQ. Inflammatory markers included serum C-reactive protein and interleukin-6 levels.\ud Results\ud A significant association was observed between IQ and harsh parenting, whereby children who were physically disciplined had lower IQ scores (accounting for relevant social factors). Both immune markers were associated with variation in cognition, however, neither accounted for the effects of ELA on cognition.\ud Discussion\ud This study highlights the impact of ELA on cognition. In the absence of evidence that these effects are explained by inflammation, other mechanisms by which the effects of ELA are mediated are discussed.

Published
2020

47. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Alexandre Reymond, Borja Rodriguez-Herreros, Stefan Ehrlich, Tiago Reis Marques, Roberto Roiz-Santiañez, Barbara Franke, Henry Brodaty, Ryota Hashimoto, Tobias Kaufmann, Thomas Gareau, Gary Donohoe, Masataka Kikuchi, David Ames, Greig I. de Zubicaray, Vince D. Calhoun, Zdenka Pausova, Anouk den Braber, Laurena Holleran, Katharina Wittfeld, Roel A. Ophoff, G. Bragi Walters, Sandra Martin-Brevet, Karen A. Mather, Dan J. Stein, Costin Leu, Rachel M. Brouwer, Norman Delanty, Nicholas G. Martin, Arvid Lundervold, Jean Shin, Geneviève Richard, Dorret I. Boomsma, Gudrun A. Jonsdottir, Emma Knowles, Margie Wright, Magnus O. Ulfarsson, Yunpeng Wang, Thomas W. Mühleisen, Vincent Frouin, Andrew J. Schork, Peter R. Schofield, Michael Andersson, Katrin Amunts, Hans J. Grabe, Wei Wen, Manon Bernard, James Rucker, Anbu Thalamuthu, Hans-Richard Brattbak, Joanne E. Curran, Hidenaga Yamamori, Bruce Pike, Brenda W.J.H. Penninx, Derek W. Morris, Masaki Fukunaga, Aiden Corvin, René S. Kahn, John Blangero, Yuri Milaneschi, Nynke A. Groenewold, Mark McCormack, Allan F. McRae, Clara Moreau, Gunter Schumann, Robin M. Murray, Bogdan Draganski, Simone Ciufolini, Carlos Prieto, Diana Tordesillas-Gutiérrez, Astri J. Lundervold, Sinead Kelly, Simon E. Fisher, Erik G. Jönsson, Stefan Johansson, Neda Jahanshad, Elena Shumskaya, Christopher D. Whelan, Tomáš Paus, Evangelos Vassos, Tetyana Zayats, Sébastien Jacquemont, Benedicto Crespo-Facorro, Erin Burke Quinlan, Anja Vaskinn, Ingrid Agartz, Knut K. Kolskår, Robin Bülow, Alexander Teumer, Sven Cichon, Neeltje E.M. van Haren, Jayne Y. Hehir-Kwa, Anders M. Dale, Nhat Trung Doan, Stephanie Le Hellard, John B.J. Kwok, Lars Nyberg, Sigrid Botne Sando, Omar Gustafsson, Gianpiero L. Cavalleri, Andreas Heinz, Ida E Sønderby, Sonja M C de Zwarte, Hreinn Stefansson, Derrek P. Hibar, Daniel Quintana, Vidar M. Steen, Jouke-Jan Hottenga, Paola Dazzan, David C. Glahn, Shareefa Dalvie, Lars T. Westlye, Nicholas B. Blackburn, Loes M. Olde Loohuis, Kari Stefansson, Dennis van der Meer, Lianne Schmaal, Anne Uhlmann, Nicola J. Armstrong, Stacy Steinberg, Christiane Jockwitz, Jarek Rokicki, Hilleke E Hulshoff, Sanjay M. Sisodiya, Anne-Marthe Sanders, Jan Haavik, Perminder S. Sachdev, Asta Håberg, Samuel R. Mathias, Dennis van 't Ent, Torill Ueland, Per Hoffmann, Terry L. Jernigan, Abdel Abdellaoui, Svenja Caspers, Sylvane Desrivières, Ole A. Andreassen, Masashi Ikeda, Paul M. Thompson, Eco J. C. de Geus, Céline S. Reinbold, Jingyu Liu, Juan M. Peralta, Sara Pudas, Jan Egil Nordvik, Srdjan Djurovic, David Mothersill, Lachlan T. Strike, Chi-Hua Chen, Jessica A. Turner, Manon H.J. Hillegers, Thomas Espeseth, Janita Bralten, Katie L. McMahon, APH - Methodology, APH - Mental Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Rafmagns- og tölvuverkfræðideild (HÍ), Faculty of Electrical and Computer Engineering (UI), Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, 16p11.2 European Consortium, for the ENIGMA-CNV working group, Child and Adolescent Psychiatry / Psychology, Epidemiology and Data Science, Neurology, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Digital Health

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), genetics [Chromosome Disorders], Pathology, Databases, Factual, Autism, Taugasjúkdómar, methods [Magnetic Resonance Imaging], 0302 clinical medicine, pathology [Basal Ganglia], pathology [Brain], methods [Image Processing, Computer-Assisted], Chromosome Duplication, Basal ganglia, pathology [Globus Pallidus], genetics [Schizophrenia], Copy-number variation, pathology [Putamen], medicine.diagnostic_test, Einhverfa, Gen, genetics [Neurodevelopmental Disorders], Putamen, Neurodevelopmental disorders, Middle Aged, Microdeletion syndrome, 3. Good health, Psychiatry and Mental health, genetics [Chromosomes, Human, Pair 16], Globus pallidus, Schizophrenia, genetics [Autism Spectrum Disorder], Female, Chromosome Deletion, Medical Genetics, Adult, Neuroinformatics, medicine.medical_specialty, genetics [DNA Copy Number Variations], Article, genetics [Autistic Disorder], 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 17 - Partnerships for the Goals, Geðklofi, medicine, Humans, ddc:610, Molecular Biology, Medicinsk genetik, CNVs, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genetics [Organ Size], business.industry, Brain morphometry, Magnetic resonance imaging, medicine.disease, 030104 developmental biology, genetics [Intellectual Disability], business, Psychiatric disorders, 030217 neurology & neurosurgery, Neuroscience
Abstract

Publisher's version (útgefin grein), Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10− 9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes., 1000BRAINS: 1000BRAINS is a population-based cohort based on the Heinz-Nixdorf Recall Study and is supported in part by the German National Cohort. We thank the Heinz Nixdorf Foundation (Germany) for their generous support in terms of the Heinz Nixdorf Study. The HNR study is also supported by the German Ministry of Education and Science (FKZ 01EG940), and the German Research Council (DFG, ER 155/6-1). The authors are supported by the Initiative and Networking Fund of the Helmholtz Association (Svenja Caspers) and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 7202070 (Human Brain Project SGA1; Katrin Amunts, Sven Cichon). This work was further supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Program (grant 01ZX1314A to M.M.N. and S.C.), and by the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). 16p.11.2 European Consortium: B.D. is supported by the Swiss National Science Foundation (NCCR Synapsy, project grant Nr 32003B_159780) and Foundation Synapsis. LREN is very grateful to the Roger De Spoelberch and Partridge Foundations for their generous financial support. This work was supported by grants from the Simons Foundation (SFARI274424) and the Swiss National Science Foundation (31003A_160203) to A.R. and S.J. Betula: The relevant Betula data collection and analyses were supported by a grant from the Knut & Alice Wallenberg (KAW) to L. Nyberg. Brainscale: the Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Dorret Boomsma), 51.02.060 (Hilleke Hulshoff Pol), 668.772 (Dorret Boomsma & Hilleke Hulshoff Pol); NWO/SPI 56-464-14192 (Dorret Boomsma), the European Research Council (ERC-230374) (Dorret Boomsma), High Potential Grant Utrecht University (Hilleke Hulshoff Pol), NWO Brain and Cognition 433-09-220 (Hilleke Hulshoff Pol). Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud university medical centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative has received supported from the participating departments and centres and from external grants, i.e., the Biobanking and Biomolecular Resources Research Infrastructure (the Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organisation for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant ‘Language in Interaction’, the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreements n° 602450 (IMAGEMEND), n°278948 (TACTICS), and n°602805 (Aggressotype) as well as from the European Community’s Horizon 2020 programme under grant agreement n° 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. COBRE: This work was supported by a NIH COBRE Phase I grant (1P20RR021938, Lauriello, PI and 2P20GM103472, Calhoun, PI) awarded to the Mind Research Network. We wish to express our gratitude to numerous investigators who were either external consultants to the Cores and projects, mentors on the projects, members of the external advisory committee and members of the internal advisory committee. Decode: The research leading to these results has received financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007–2013), EU-FP7 funded grant no. 602450 (IMAGEMEND) as well as support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no.115300 (EUAIMS). DemGene: Norwegian Health Association and Research Council of Norway. Dublin: Work was supported by Science Foundation Ireland (SFI grant 12/IP/1359 to Gary Donohoe and SFI08/IN.1/B1916-Corvin to Aidan C Corvin) and the European Research Council (ERC-StG-2015-677467). EPIGEN-UK (SMS, CL): The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner, and the Epilepsy Society for supporting CL. Haavik: The work at the K.G.Jebsen center for neuropsychiatric disorders at the University of Bergen, Norway, was supported by Stiftelsen K.G. Jebsen, European Community’s Seventh Framework Program under grant agreement no 602805 and the H2020 Research and Innovation Program under grant agreement numbers 643051 and 667302. HUNT: The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. IMAGEN: The work received support from the European Union-funded FP6Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), the FP7 projects IMAGEMEND (602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-1, SM 80/7-2, SFB 940/1). Further support was provided by grants from: ANR (project AF12-NEUR0008-01—WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. MCIC: This work was supported primarily by the Department of Energy DE-FG02-99ER62764 through its support of the Mind Research Network and the consortium as well as by the National Association for Research in Schizophrenia and Affective Disorders (NARSAD) Young Investigator Award (to SE) as well as through the Blowitz-Ridgeway and Essel Foundations, and through NWO ZonMw TOP 91211021, the DFG research fellowship (to SE), the Mind Research Network, National Institutes of Health through NCRR 5 month-RR001066 (MGH General Clinical Research Center), NIMH K08 MH068540, the Biomedical Informatics Research Network with NCRR Supplements to P41 RR14075 (MGH), M01 RR 01066 (MGH), NIBIB R01EB006841 (MRN), R01EB005846 (MRN), 2R01 EB000840 (MRN), 1RC1MH089257 (MRN), as well as grant U24 RR021992. NCNG: this sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the K.G. Jebsen Foundation, the Research Council of Norway, to SLH, VMS and TE. The Bergen group was supported by grants from the Western Norway Regional Health Authority (Grant 911593 to AL, Grant 911397 and 911687 to AJL). NESDA: Funding for NESDA was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health.Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. NTR: The NTR study was supported by the Netherlands Organization for Scientific Research (NWO), MW904-61-193 (Eco de Geus & Dorret Boomsma), MaGW-nr: 400-07- 080 (Dennis van ‘t Ent), MagW 480-04-004 (Dorret Boomsma), NWO/SPI 56-464-14192 (Dorret Boomsma), the European Research Council, ERC-230374 (Dorret Boomsma), and Amsterdam Neuroscience. OATS: OATS (Older Australian Twins Study) was facilitated by access to Twins Research Australia, which is funded by a National Health and Medical Research Council (NHMRC) Enabling Grant 310667. OATS is also supported via a NHMRC/Australian Research Council Strategic Award (401162) and a NHMRC Project Grant (1045325). DNA extraction was performed by Genetic Repositories Australia, which was funded by a NHMRC Enabling Grant (401184). OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. PAFIP: PAFIP data were collected at the Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Carlos III Health Institute PIE14/00031 and SAF2013-46292-R and SAF2015-71526-REDT. We wish to acknowledge IDIVAL Neuroimaging Unit for imaging acquirement and analysis.We want to particularly acknowledge the patients and the BioBankValdecilla (PT13/0010/0024) integrated in the Spanish National Biobanks Network for its collaboration. QTIM: The QTIM study was supported by grants from the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) (486682, 1009064). Genotyping was supported by NHMRC (389875). Lachlan Strike is supported by an Australian Postgraduate Award (APA). AFM is supported by NHMRC CDF 1083656. We thank the twins and siblings for their participation, the many research assistants, as well as the radiographers, for their contribution to data collection and processing of the samples. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403 and 01ZZ0701), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. StrokeMRI: StrokeMRI has been supported by the Research Council of Norway (249795), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073) and the Norwegian ExtraFoundation for Health and Rehabilitation. TOP: TOP is supported by the Research Council of Norway (223273, 213837, 249711), the South East Norway Health Authority (2017-112), the Kristian Gerhard Jebsen Stiftelsen (SKGJ‐MED‐008) and the European Community’s Seventh Framework Programme (FP7/2007–2013), grant agreement no. 602450 (IMAGEMEND). We acknowledge the technical support and service from the Genomics Core Facility at the Department of Clinical Science, the University of Bergen

Published
2020

48. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinos Constantinides, Laura KM Han, Clara Alloza, Linda Antonucci, Celso Arango, Rosa Ayesa-Arriola, Nerisa Banaj, Alessandro Bertolino, Stefan Borgwardt, Jason Bruggemann, Juan Bustillo, Oleg Bykhovski, Vaughan Carr, Stanley Catts, Young-Chul Chung, Benedicto Crespo-Facorro, Covadonga M Díaz-Caneja, Gary Donohoe, Stefan Du Plessis, Jesse Edmond, Stefan Ehrlich, Robin Emsley, Lisa T Eyler, Paola Fuentes-Claramonte, Foivos Georgiadis, Melissa Green, Amalia Guerrero-Pedraza, Minji Ha, Tim Hahn, Frans A Henskens, Laurena Holleran, Stephanie Homan, Philipp Homan, Neda Jahanshad, Joost Janssen, Ellen Ji, Stefan Kaiser, Vasily Kaleda, Minah Kim, Woo-Sung Kim, Matthias Kirschner, Peter Kochunov, Yoo Bin Kwak, Jun Soo Kwon, Irina Lebedeva, Jingyu Liu, Patricia Mitchie, Stijn Michielse, David Mothersill, Bryan Mowry, Víctor Ortiz-García de la Foz, Christos Pantelis, Giulio Pergola, Fabrizio Piras, Edith Pomarol-Clotet, Adrian Preda, Yann Quidé, Paul E Rasser, Kelly Rootes-Murdy, Raymond Salvador, Marina Sangiuliano, Salvador Sarró, Ulrich Schall, André Schmidt, Rodney J Scott, Pierluigi Selvaggi, Kang Sim, Antonin Skoch, Gianfranco Spalletta, Filip Spaniel, Sophia I. Thomopoulos, David Tomecek, Alexander S Tomyshev, Diana Tordesillas-Gutiérrez, Therese van Amelsvoort, Javier Vázquez-Bourgon, Daniela Vecchio, Aristotle Voineskos, Cynthia S Weickert, Thomas Weickert, Paul M Thompson, Lianne Schmaal, Theo GM van Erp, Jessica Turner, James H Cole, Danai Dima, and Esther Walton

Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen’s d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2022

49. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022

50. Thirteen Independent Genetic Loci Associated with Preserved Processing Speed in a Study of Cognitive Resilience in 330,097 Individuals in the UK Biobank

Author

Pilib Ó Broin, Derek W. Morris, Joan Fitzgerald, Gary Donohoe, Laura Fahey, and Laurena Holleran

Subjects
Multifactorial Inheritance, Genome-wide association study, Biology, QH426-470, Polymorphism, Single Nucleotide, Article, functional analysis, Cognition, Memory, Adaptation, Psychological, genomics, Genetics, Humans, processing speed, Genetic Predisposition to Disease, Effects of sleep deprivation on cognitive performance, Cognitive skill, Cognitive decline, Resilience (network), Genetics (clinical), Biological Specimen Banks, cognitive resilience, healthy aging, proxy phenotypes, Middle Aged, Resilience, Psychological, Biobank, United Kingdom, Genetic Loci, Neuron differentiation, Neuroscience, Psychomotor Performance
Abstract

Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. UK Biobank (UKB) does not have direct measurements of the same cognitive phenotype at distal timepoints. Therefore, we used number of education years (EY) as a proxy phenotype for past cognitive performance. Current cognitive performance was determined based on processing speed. This approach captured an average time span of 40 years between past and current cognitive performance in 330,097 individuals. A confounding factor was that EY is highly polygenic and masked the genetics of resilience. To overcome this, we employed Genomics Structural Equation Modelling (GenomicSEM) to perform a GWAS-by-subtraction using two GWAS, one GWAS of EY and resilience and a second GWAS of EY but not resilience. Subtracting one from the other generated a GWAS of Resilience. Replication of this approach was shown using independent discovery and replication samples and the full GWAS results were examined further using functional genomics analysis. We found 13 independent genetic loci for Resilience. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59×10−8) and glutamatergic neurons (P=6.98×10−6) in the cortex. Gene-set analyses implicated the biological process “neuron differentiation” (P=9.7×10−7) and the cellular component “synaptic part” (P=2.14×10−6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience. Author Summary We all differ in our levels of resilience to cognitive decline as we age. We know that a healthy lifestyle protects us from cognitive decline, however we do not know the role that our genes play in this process. By identifying the genes involved, we can then examine their biology, which could point to therapeutic interventions that may increase our resilience. To study the genetics of cognitive resilience we need large datasets with the same measures of cognitive performance over a long period of time. That data are currently not available, even within large biobanks. Instead, we used a measure of processing speed for current cognitive performance and number of years in education as a proxy measure of past cognitive performance to study genes associated with resistance over time in 330,097 individuals from the UK Biobank. After testing our method to show its replicability, we identified 13 genetic regions containing many genes that were associated with resilience. We showed that these genes function in several brain regions and different cell types. We also showed that white matter volume in the brain affects resilience. This study increases our biological understanding of resilience.

Published
2022

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